NEW YORK (GenomeWeb) – Kura Oncology this week presented data demonstrating that its drug tipifarnib had promising activity in patients with advanced T-cell lymphomas, particularly when they have certain CXCL12 pathway biomarkers.
On a conference call ahead of a presentation at the European Hematology Association's annual congress in Amsterdam, Kura CEO Troy Wilson said these are the first data demonstrating that biomarkers in the CXCL12 pathway enrich for activity to tipifarnib in peripheral T-cell lymphoma patients and a subset of patients with angioimmunoblastic T-cell lymphoma. The company is discussing this data on the CXCL12 inhibitor with regulatory authorities.
The level of efficacy seen in the present Phase II study also gives Kura confidence to pursue development of its investigational drug in other cancers with CXCL12 expression, including acute myeloid leukemia, diffuse large B-cell lymphoma (DLBCL), and pancreatic cancer, company executives said during the call.
This year, around 74,000 patients will be diagnosed with non-Hodgkins lymphoma in the US, and four percent of these patients will have a subtype of NHL called peripheral T-cell lymphoma (PTCL). Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive form of PTCL, accounting for 18 percent of PTCL cases, and these patients often have autoimmune disorders that cause their own immune systems to attack red blood cells and platelets. Initial treatments for PTCL and AITL usually involve multiple chemotherapy regimens. There are histone deacetylase inhibitors approved for relapsed patients, and treatments after relapse for AITL can include chemotherapy followed by stem cell transplants using patients' own cells or donor cells.
In a multi-center, single-arm, Phase II trial, researchers from Kura initially enrolled relapsed or refractory PTCL patients without biomarker selection. However, based on molecular characterization of 18 patients' cancers, Kura launched two expanded cohorts, one cohort enrolled 16 patients with AITL characterized by high levels of CXCL12 expression and a second cohort of 15 PTCL patients who are wildtype or don't have a mutation in the 3'-untranslated region of the CXCL12 gene.
Around 35 percent of PTCL patients and half of AITL patients have high CXCL12 expression, which is associated with worse prognosis. Tipifarnib is hypothesized to work in this subset of patients by inhibiting CXCL12.
In total, there were CXCL12 expression data in 34 PTCL patients, and 17 had a high ratio of CXCL12 expression to its receptor CXCR4, and in this subset, the overall response rate was 47 percent. In the CXCL12-expressing AITL cohort, out of 11 evaluable patients, the overall response rate was 45 percent.
In a dozen evaluable PTCL patients with wildtype CXCL12 3'UTR in the second cohort, the overall response rate was 42 percent. When researchers looked at six PTCL patients with a mutation in this region of the gene — the CXCL12 rs2839695 A/G or G/G genotype — none responded to tipifarnib.
Researchers also looked at a subset of AITL patients with KIR3DL2 mutations and saw very promising responses. While CXCL12 expression is a marker for sensitivity to tipifarnib, CXCL5 expression is a resistance marker for the drug. However, next-generation sequencing of 16 AITL patients revealed that around 50 percent had KIR3DL2 mutations and low CXCL5 expression.
In the trial, among eight patients with this mutation the overall response rate to tipifarnib was 75 percent. In eight AITL patients who didn't have this mutation the response rate was 25 percent. The researchers further noted that high KIR3DL2 mutant variant allele frequency appeared to be predictive of which AITL patients experienced a complete response to tipifarnib.
"It's easy to get lost in these different subtypes of PTCL, but the reality is, no matter how you cut the data, we're getting positive results," Wilson said. Kura is talking with regulators about which biomarker-defined population to prioritize for registration studies and what types of studies are needed.
There are a number of strategies that may be possible next for tipifarnib. The company could launch an AITL study that enrolls all comers and then retrospectively looks for response according to the presence or absence of a KIR3DL2 mutation. This type of a strategy may be feasible for a registrational trial for accelerated approval, according to Wilson, given the level of response seen to the drug in the present study in fourth-line AITL.
In PTCL patients characterized by mutated or wildtype CXCL12 3'UTR, regulators may want to see a randomized trial. While Wilson noted that Kura would prefer to do single-arm response-driven trials initially, "we certainly wouldn't shy away from a randomization if we needed to."
Although the CXCL12 biomarkers explored in the Phase II study identify rare subpopulations of T-cell lymphoma patients, Wilson said that there was no difficulty identifying these patients using molecular tools. "We're building a tool set that's not only useful for T-cell lymphoma but for other diseases as well," he said, noting that miRNA expression profiling, next-generation sequencing tests, and immunohistochemistry could all be used to identify the intended use population for tipifarnib.
While researchers used a combination of molecular technologies in the Phase II studies, a Kura spokesperson said the company has a preference for tumor NGS testing of KIR3DL2 and CXCL12 3'UTR. Commercially available NGS panels, such as Foundation Medicine's FoundationOne CDx, don't currently feature analysis of CXCL12 or KIR3DL2.
However, test providers aren't opposed to adding these genes to their panel if it can help guide treatment, according to Antonio Gualberto, Kura's chief medical officer. Providers of NGS panels are naturally interested in having genes that are associated with response to a drug, he said, and the company is already in discussions with test developers about the markers important to tipifarnib response.
If tipifarnib successfully reaches the market, it will be another example of a drug that genomics and molecular tools rescued. J&J abandoned the drug after it failed to garner FDA approval in 2005 for AML, but Kura bought it and pursued a molecularly informed strategy in head and neck cancer patients with HRAS mutations. Tipifarnib has shown a 45 percent response rate in this setting and has entered registrational studies.
Kura has plans to explore the activity of tipifarnib in biomarker-defined populations in several other cancer settings. "We started in T-cell lymphoma because that was the easiest place to identify the biomarkers of activity and validate them in terms of enrichment of clinical benefit," Wilson said.
However, CXCL12 expression is increased in around a third of pancreatic cancers, AML, and DLBCL. Kura executives said researchers have confidence they'll be able to predict complete responders to tipifarnib in AML patients using a molecularly guided strategy. The company has already committed itself to doing a proof-of-concept trial for tipifarnib in pancreatic cancer.
"We continue to develop a set of tools, including genetic markers, that will allow us to very rationally … extend what we're doing in T-cell lymphoma to these other diseases," Wilson said. "Now, we have a clear path. We have mutations and variations that seem to consistently predict clinical benefit."
While a molecular-defined drug development strategy may cut into the size of the intended use population for a drug in a particular disease setting, the level of benefit from tipifarnib in the subsets of PTCL patients suggests that Kura may be able to distinguish its product in the market. "We increasingly operate in a world where people are looking at the cost of drugs and the clinical benefit," Wilson said. "And, certainly, if you can drive response rates of 40 percent and complete response rates of 50 percent [in PTCL and AITL], you're definitely within a realm of being able to command premium pricing."